TMPRSS6 rs2235321: Iron Status and Anemia Risk
The genetic variant rs2235321 is a single nucleotide polymorphism located in an exon of the TMPRSS6 gene, which encodes matriptase-2—a key regulator of systemic iron balance. Genome-wide and candidate gene studies have linked this variant to modest shifts in iron biomarkers, such as transferrin saturation and mean corpuscular volume (MCV), as well as susceptibility to iron deficiency anemia. Because rs2235321 is a synonymous change that does not alter the protein sequence, its biological effect is modest and evidence regarding its clinical impact remains limited.
What each genotype means
Lower hepcidin levels
Research indicates that individuals with this genotype may exhibit lower plasma hepcidin concentrations compared to those with the GG genotype. While this association has been observed in some populations, the overall impact on iron status markers remains subtle and contributes only a small amount to population-level variance.
This genotype is common, as the minor allele frequency for this variant is approximately 0.40–0.48 in many global populations.
Intermediate hepcidin profile
This genotype represents a heterozygous state for the rs2235321 variant. Studies suggest that the influence of this variant on iron regulation is subtle, and carriers of this genotype typically show intermediate hepcidin levels compared to the homozygous groups.
This is a very common genotype, occurring frequently across diverse global populations due to the high prevalence of both alleles.
Baseline hepcidin levels
Individuals with this genotype are considered to have the baseline or reference profile for this specific variant in the context of hepcidin regulation. Research suggests that carriers of this genotype may have higher hepcidin levels compared to those with the AA genotype, though the clinical significance of this difference is considered minor.
This genotype is common, reflecting the high frequency of the G allele in global populations.
What Is rs2235321 and Where Is It Located?
The single nucleotide polymorphism rs2235321 is situated on chromosome 22 within an exon of the TMPRSS6 gene. On the coding strand, it represents a synonymous base substitution often annotated as c.2217C>T (p.Tyr739=), though it can also be recorded in complementary or forward formats (such as G and A alleles depending on database orientation). Because it is a synonymous variant, the change preserves the encoded amino acid tyrosine in the resulting polypeptide. While synonymous variants were historically presumed to be biologically silent, modern genomic research demonstrates that they can occasionally influence gene expression by modifying mRNA secondary structure, altering splicing regulatory motifs, or affecting translation kinetics. In many genomic analyses, rs2235321 also exists in varying degrees of linkage disequilibrium with other widely studied functional TMPRSS6 polymorphisms, including the nonsynonymous variant rs855791.
The Biological Role of TMPRSS6 and Matriptase-2
The TMPRSS6 gene provides instructions for producing matriptase-2, a type II transmembrane serine protease expressed predominantly in the liver. Matriptase-2 plays a foundational role in human iron homeostasis by cleaving membrane-bound hemojuvelin (HJV), an essential co-receptor for the bone morphogenetic protein (BMP) signaling pathway. By degrading hemojuvelin, matriptase-2 suppresses the transcription of HAMP, the gene that produces hepcidin. Hepcidin is the master systemic iron-regulatory hormone that binds to and induces the degradation of ferroportin, the sole known cellular iron exporter found on intestinal enterocytes and recycling macrophages. When matriptase-2 activity decreases, hepcidin levels can remain inappropriately high, trapping iron within cells and reducing systemic iron availability. Rare pathogenic loss-of-function mutations in TMPRSS6 lead to iron-refractory iron deficiency anemia (IRIDA), while common polymorphisms generally exert subtler regulatory influences on iron parameters.
Research Associations and Evidence Strength
Genome-wide association studies (GWAS) and targeted nutrigenomic cohorts have evaluated rs2235321 alongside other candidate TMPRSS6 single nucleotide polymorphisms. Multiple investigations have reported associations between the minor allele and alterations in hematological traits, including lower transferrin saturation (TSAT), diminished mean corpuscular volume (MCV), and an elevated risk of developing iron deficiency anemia. However, the scientific evidence supporting an independent functional role for rs2235321 is currently classified as limited. Several studies indicate that rs2235321 often acts in tandem with nearby nonsynonymous variants like rs855791, making it challenging to isolate its individual biological effect. Furthermore, cross-population investigations—including clinical trials and recall-by-genotype studies in West African and European cohorts—demonstrate that statistical associations can be population-specific and may not consistently produce noticeable differences in oral iron absorption or systemic hepcidin modulation.
Navigating Dietary and Clinical Implications
Possessing a variant allele at rs2235321 does not mean you have or will inevitably develop iron deficiency anemia. Common genetic variants in TMPRSS6 typically contribute very small effect sizes to overall iron traits, which are heavily shaped by nongenetic factors such as dietary iron intake, bioavailability, chronic blood loss, systemic inflammation, and menstrual status. This genetic data is strictly educational and cannot be used to diagnose anemia, monitor iron stores, or justify self-directed high-dose iron supplementation, which carries toxicity risks like gastrointestinal distress and organ damage. If you are experiencing symptoms of fatigue, pallor, or weakness, standard diagnostic blood tests—such as a complete blood count (CBC), serum ferritin, and transferrin saturation—remain the gold standard for clinical assessment. Always consult a licensed healthcare professional or registered dietitian before changing your nutritional approach or starting therapeutic iron supplements.
How common is this variant?
The minor allele frequency for rs2235321 ranges broadly between approximately 0.40 and 0.48 across global populations, meaning both heterozygotes and homozygotes are widely represented across diverse ancestral backgrounds.
Frequently asked questions
Does having the rs2235321 variant mean I have iron deficiency anemia?
No. The rs2235321 variant is a common genetic marker linked only to minor statistical variations in iron parameters across large population groups. Having one or two copies of the minor allele does not cause clinical anemia on its own, which depends heavily on dietary iron intake, absorption, and overall health.
Can I take iron supplements based solely on my rs2235321 genotype?
No. Genetic testing should never be used as a reason to begin therapeutic iron supplements. Excess iron can accumulate in vital organs and cause toxicity; any supplementation should be guided by objective blood tests, such as serum ferritin and transferrin saturation, under medical supervision.
What is the biological difference between rs2235321 and rs855791?
While both reside within the TMPRSS6 gene, rs855791 causes an amino acid substitution (A736V) that directly changes the catalytic activity of matriptase-2. In contrast, rs2235321 is a synonymous variant that does not alter the protein sequence, and its observed effects may partly stem from being co-inherited with other functional variants.
What blood tests should I get if I am concerned about my iron levels?
To evaluate your actual iron status, talk to your doctor about comprehensive blood work. A standard evaluation typically includes a complete blood count (measuring hemoglobin, hematocrit, and mean corpuscular volume) along with an iron panel assessing serum iron, total iron-binding capacity, transferrin saturation, and ferritin.
Sources & further reading
Educational information only, last refreshed 9/5/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Modulates matriptase-2 regulation of hepcidin expression, influencing systemic iron status and individual susceptibility to dietary iron deficiency.
This SNP is a well-established marker associated with iron status and hemoglobin levels.